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* 5-Nitroindirubin-3′-oxime. A treatment with this small molecule leads to inhibition of cyclin D1 and thus inhibition of proliferation. Skin cancers are the most common malignancies in the world. Among the most frequent skin cancer entities, squamous cell carcinoma (SCC) ranks second (~20%) after basal cell carcinoma (~77%). In early stages, a complete surgical removal of the affected tissue is carried out as standard therapy. Knowledge of characteristic molecular alterations in certain cancer entities, such as SCC, can help identify tumor-specific substances for targeted therapies. Most frequently, altered genes in SCC include TP53, NOTCH, EGFR, and CCND1. For example, the gene CCND1, which codes for cyclin D1 protein, is upregulated in nearly half of SCC cases and promotes proliferation of affected cells. As a component of Danggui Longhui Wan, a traditional Chinese medicine, indirubins are used to treat chronic diseases and have been shown to inhibit inflammatory reactions. Indirubins are pharmacologically relevant small molecules with proapoptotic and antiproliferative activity. ( https://doi.org/10.3390/cancers13081770 )
* A-438079 is a selective P2X7 purinoceptor antagonist in both human and rat with minimal activity at 75 different G-protein-coupled receptors, enzymes, transporters, and ion channels tested. A-438079 molecule, one of the most potent and selective antagonists that competitively blocks P2X7 receptor in vitro activation and produces anti-nociceptive effects in in vivo settings. In addition to nociception, A438079 has already been successfully used in in vivo models of hyperalgesia, epilepsy, Parkinson’s disease, salivary gland exocrinopathy, and Charcot-Marie-Tooth 1A disease.
* Aceclidine is a small molecule acetylcholinesterase receptor agonist that causes pupil contraction, or miosis, creating a pinhole effect that improves near vision. Studies have shown that aceclidine’s mechanism of action is differentiated from competing therapeutic options due to its ability to create a pinhole pupil effect while avoiding myopic shift. It is crucial to minimize myopic shift as it can significantly impair distance vision for a majority of presbyopes. Aceclidine’s unique MOA, in which miosis is decoupled from myopic shift, is expected to allow it to target the broadest patient population. In the phase 2 trial, the near vision improvement was due to aceclidine’s ability to maintain a pinhole pupil sweet spot of 1.5 mm to 2 mm for 7 hours. There was no loss and a slight trend toward net gain in best corrected distance vision. In addition, aceclidine was well tolerated with most common side effect being mild discomfort on instillation and no serious adverse events. Aceclidine has been marketed in Europe but has not been used clinically in the United States. It is used in the treatment of open-angle glaucoma and is a parasympathomimetic agent.
* ANA-12 is a selective, small-molecule non-competitive antagonist of TrkB, the main receptor of brain-derived neurotrophic factor (BDNF). The compound crosses the blood-brain-barrier and exerts central TrkB blockade. It blocks the neurotrophic actions of BDNF without compromising neuron survival. ANA-12 produces rapid antidepressant- and anxiolytic-like effects in animal models, the former of which have been elucidated to be mediated by blockade of BDNF signaling in the nucleus accumbens. It has also been found to alleviate methamphetamine-induced depression-like behavior (including anhedonia), behavioral sensitization, and nucleus accumbens neuroplasticity changes with subchronic (14-day) administration in mice. ANA-12 blocks the cognitive-enhancing effects of environmental enrichment and calorie restriction in rodents, which are mediated by BDNF signaling through TrkB in the hippocampus. It also blocks hippocampal neurogenesis induced by physical exercise in rodents, and may block the cognitive-enhancing effects of exercise as well.
* ATX-LPA-LPARs Inhibitors. The ATX/LPA/LPARs axis could be part of an unexplored pro-fibrotic program in skeletal muscle pathologies causing muscular fibrosis such as DMD and Limb-girdle MD. Studies that modulate the function or the presence/absence of LPA receptors yielded the most promising results that suggest a role for the ATX/LPA/LPARs axis in fibrosis pathogenesis. There is increasing data suggesting that pharmacological blockage or genetic deletion of LPA receptors could prevent the development of induced fibrosis in different organs. The primary LPA receptors that appeared to be involved in fibrosis are LPA1 and LPA3. An increasing amount of evidence places LPA as a potent modulator of inflammation in different tissues such as lung, liver, cancer-related-organs, skeletal muscle such as in chronic injury of the rotator cuff muscles and, the heart in myocardial infarction. The recording plays the sound frequencies of PF-8380 (ATX inhibitor), Ki-16425 (LPA1 and LPA3 inhibitor), VPC-12259 (LPA1and LPA3 inhibitor) and, AM-095 (LPA1 inhibitor.)
-PF-8380 is a potent orally bioavailable inhibitor of autotaxin (ATX), the enzyme that synthesize lysophosphatidic acid (LPA) from lysophosphatidyl choline, and is an emerging target for treatment of inflammatory conditions, including cancer, arthritis and multiple sclerosis. PF-8380 blocks inflammation-induced LPA synthesis. PF-8380 works both in vitro and in vivo through direct inhibition of autotaxin. In human whole blood PF-8380 inhibited autotaxin with an IC50 of 101 nM.
-Ki-16425 is an antagonist of LPA1 and LPA3 receptors with moderate activity against LPA2. Ki-16425 inhibition of LPA receptors 1 and 3 prevents the induction of CCN2 by TGF-β. Ki16425 also downregulates the SMAD 2/3 proteins.
-VPC-12249 reduces collagen deposition and prevents the induction of pro-fibrotic cytokines such as CCN2 and TGF-β in the lung.
-AM-095, an LPA1 inhibitor, causes motor skills improvement evaluated by grip strength, rotarod, and runtime.
( https://doi.org/10.1007/s12079-021-00610-w )
* BMP6 Deficiency in diabetics causes delay in bone fracture consolidation. The categories of bone fracture are the following: Closed or open fractures; complete fractures; displaced fractures; partial fractures; stress fractures. Some extra terms must also be added to describe partial, complete, open, and closed fractures. These terms include avulsion; comminuted; compression; impacted; oblique; spiral; transverse. Most often, bone fractures happen because the bone runs into a stronger force. Repetitive forces, such as running, can also fracture a bone (stress fractures). Another reason for fractures is osteoporosis, which weakens bones as you age. Internal fixation for nonunions should provide sufficient stability for fracture healing without excessive rigidity. The choice of internal fixation depends on the type of nonunion, the condition of the soft tissues and bone, the size and position of the bone fragments, and the size of the bony defect.
* BMP9-Leptin when combined might improve fracture healing. The categories of bone fracture are the following: Closed or open fractures; complete fractures; displaced fractures; partial fractures; stress fractures. Some extra terms must also be added to describe partial, complete, open, and closed fractures. These terms include avulsion; comminuted; compression; impacted; oblique; spiral; transverse. Most often, bone fractures happen because the bone runs into a stronger force. Repetitive forces, such as running, can also fracture a bone (stress fractures). Another reason for fractures is osteoporosis, which weakens bones as you age. Internal fixation for nonunions should provide sufficient stability for fracture healing without excessive rigidity. The choice of internal fixation depends on the type of nonunion, the condition of the soft tissues and bone, the size and position of the bone fragments, and the size of the bony defect.
* Bocidelpar sulfate (ASP0367) is an orally administered small molecule that potently and selectively modulates peroxisome proliferator-activated receptor δ (PPARδ) to address mitochondrial dysfunction occurring in diseases including primary mitochondrial myopathy and Duchenne muscular dystrophy. The PPAR–δ pathway regulates mitochondria by turning on different genes in the cell. When the pathway is on, the mitochondria use fatty acids more often and more mitochondria are made. Using more fatty acids for energy results in increased energy production. Mitochondria are specialized structures within cells that supply chemical energy to power the activities of the cells, such as repairing muscle cells. Individuals with Duchenne lack efficient mitochondria in their cells. It is thought that by increasing or enhancing the mitochondria in muscle cells, the cellular functions of the muscle could be improved.
* Brimochol or Carbachol-Brimonidine tartrate is a miotic-based eye drop for presbyopia. Miotic agents like carbachol constrict the pupil to induce what’s called the “pinhole effect.” Similar to reducing the aperture of a camera, shrinking the pupil brings near images into clearer focus. Brimonidine dampens headache or brow ache, myopic shift, eye redness, or a loss of distance visual acuity reported by patients who take single-agent miotics. Brimonidine inhibits the contraction of the ciliary muscle, which means patients end up with a drug that gives them this meiosis, this pinhole effect, without the unwanted side effects. The effect could last at least eight hours. Carbachol is a parasympathomimetic that mimics the effect of acetylcholine on both the muscarinic and nicotinic receptors. This drug is administered ocularly to induce miosis to reduce intraocular pressure in the treatment of glaucoma. Carbachol is also used to stimulate micturition by contraction of detrusor muscle. This drug may cause hypotension, bradycardia, nausea, vomiting, bronchospasm, and abdominal cramps. Carbachol is an ammonium salt and a carbamate ester. It has a role as a nicotinic acetylcholine receptor agonist, a muscarinic agonist, a non-narcotic analgesic, a cardiotonic drug and a miotic. Cholinergic, parasympathomimetic, used chiefly in large animals, especially for colic in the horse. (EPA, 1998). Brimonidine tartrate is the tartrate salt form of brimonidine, an imidazole derivative and a selective alpha-2 adrenergic receptor agonist. Upon ocular administration, brimonidine tartrate acts on the blood vessels causing them to constrict which leads to a decrease in the production of aqueous humor. Brimonidine tartrate also enhances the outflow of aqueous humor. This drug is used in the treatment of glaucoma to reduce intraocular pressure. A quinoxaline derivative and adrenergic alhpa-2 receptor agonist that is used to manage intraocular pressure associated with open-angle glaucoma and ocular hypertension.
* C004019 is a small molecule designed on the basis of Proteolysis Targeting Chimera (PROTAC) to selectively enhance ubiquitination and proteolysis of tau proteins. C004019 robustly promotes tau clearance in multiple tau-overexpressing cell models via ubiquitination-proteasome pathway. Furthermore, both intracerebral and subcutaneous administration of C004019 could also remarkably reduce tau level in wild-type, human tau (hTau) transgenic and 3xTg-AD mouse models with simultaneous amelioration of synaptic and cognitive functions.Increasing evidence suggests that intracellular accumulation of tau plays a pivotal role in neurodegeneration and memory deficits in AD and the related neurodegenerative disorders, collectively termed tauopathies. The chimera is composed of three parts including a tau binder, a linker and an E3 ligase recruiter or Vhl binder, in which the two functional parts respectively binds to tau proteins and E3 ligase to reach a selective and efficient ubiquitination and the subsequent proteasome-mediated proteolysis of tau. In vitro and in vivo testing C004019 shows it efficiently induces clearance of tau proteins in both physiological and pathological conditions. Remarkably, even single-dose or infrequently (once per 6 days) subcutaneous administration of this molecule achieved a sustained tau reduction in the brain of hTau and 3xTg-AD transgenic mouse models. Lowering tau can alleviate Aβ-induced neurotoxicity, and knockdown of tau does not elicit obvious abnormalities in mice. ( https://www.thno.org/v11p5279.htm )
* CD2019 overcomes inhibition of axonal outgrowth via phosphoinositide 3-kinase signalling in the injured adult spinal cord. After spinal cord injury in the adult mammal, axons do not normally regrow and this commonly leads to paralysis. Retinoic acid (RA) can stimulate neurite outgrowth in vitro of both the embryonic central and peripheral nervous system, via activation of the retinoic acid receptor (RAR) beta2. Spinal cord injuries (SCIs) often result in permanent damage in the adult due to the very limited capacity of axonal regeneration. Intrinsic neuronal programs and the formation of a glial scar are the main obstacles. Activation of RARβ in the neuron inactivates phosphatase and tensin homolog and induces its transfer into the astrocytes in small vesicles, where it prevents scar formation.
* Coenzyme CoQ10 (ubiquinone) is present in all respiring eukaryotic cells, primarily in the mitochondria. It is a component of the electron transport chain and participates in aerobic cellular respiration, which generates energy in the form of ATP. Ninety-five percent of the human body's energy is generated this way. Organs with the highest energy requirements—such as the heart, liver, and kidney—have the highest CoQ10 concentrations. n a 2017 meta-analysis of people with heart failure 30–100 mg/d of CoQ10 resulted in 31% lower mortality. Exercise capacity was also increased. The Canadian Headache Society guideline for migraine prophylaxis recommends, based on low-quality evidence, that CoQ10 be offered as a choice for prophylaxis. A 2018 meta-analysis concluded that there was preliminary evidence for oral CoQ10 reducing statin-associated muscle symptoms, including muscle pain, muscle weakness, muscle cramps and muscle tiredness. CoQ10 may reduce the effectiveness of chemo and radiation therapy, so most oncologists would recommend avoiding it during cancer treatment. A 1995 review study found that there is no clinical benefit to the use of CoQ10 in the treatment of periodontal disease. When applied topically in skincare products it demonstrates some ability to reduce oxidative stress in the skin, delay signs of intrinsic skin aging, reverse signs of extrinsic skin aging, assist in fading dyspigmentation, increase stability of certain sunscreen actives, increase the SPF of sunscreens, and afford some infrared protection to sunscreens. Much of the research on the skin benefits of ubiquinone show that it works synergistically with other topical antioxidants to improve the skin and cosmetic formulations. Coenzyme Q10 has potential to inhibit the effects of theophylline as well as the anticoagulant warfarin; coenzyme Q10 may interfere with warfarin's actions by interacting with cytochrome p450 enzymes thereby reducing the INR, a measure of blood clotting. The structure of coenzyme Q10 is very similar to that of vitamin K, which competes with and counteracts warfarin's anticoagulation effects. Coenzyme Q10 should be avoided in patients currently taking warfarin due to the increased risk of clotting.
* D-Pantothenic Acid (pantothenate, vitamin B5) is a water-soluble vitamin ubiquitously found in plants and animal tissues with antioxidant property. Vitamin B5 is a component of coenzyme A (CoA) and a part of the vitamin B2 complex. Vitamin B5 is a growth factor and is essential for various metabolic functions, including the metabolism of carbohydrates, proteins, and fatty acids. This vitamin is also involved in the synthesis of cholesterol, lipids, neurotransmitters, steroid hormones, and hemoglobin. Only the dextrorotatory (D) isomer of pantothenic acid possesses biological activity. while the levorotatory (L) form may antagonize the effects of the dextrorotatory isomer.
* Duchenne Mix for Duchenne muscular dystrophy (DMD) is,
-Ubiquinone (co-enzyme Q10), a key component of an energy pathway in the mitochondria, called the electron transport chain.
-Edasalonexent, a small molecule that inhibits a protein called NF-kappa B in the NF-kappa B pathway. This pathway is activated in people with Duchenne muscular dystrophy (DMD), resulting in muscle fiber breakdown and the inability to repair muscle injuries.
-Ezutromid upregulates the production of utrophin to substitute for the deficiency of dystrophin in people with DMD. Utrophin upregulation is an actively researched therapeutic approach for the treatment of DMD. Utrophin is similar to dystrophin, but is produced only during embryonic development. It is hypothesized that increased utrophin during adulthood can compensate for the lack of dystrophin in DMD patients.
-MNK-1411 is the synthetic equivalent of the adrenocorticotropic hormone. It is a synthetic melanocortin agonist — a substance that acts like another substance, stimulating an action — that acts on melanocortin receptors. It delays the progression of DMD by modulating immune system activity and reducing muscle inflammation.
* E-64 is a small molecule inhibitor exhibiting the activity against African swine fever virus protease pS273R. The pS273R protein of the African swine fever virus (ASFV) is a specific SUMO-1-like cysteine protease that plays an important role in its replication process. To inhibit virus replication and improve treatment options the 14th carbon atom of the cysteinase inhibitor E-64 could form one Csingle bondS covalent bond with the Cys 232 amino acid of the pS273R protease and seven additional hydrogen bonds to maintain a stable binding state. E-64 could effectively inhibit the enzyme activity center of the pS273R protease by preventing pS273R protease from lysing pp62, while promoting the upregulation of immune-related cytokines at the transcription level. Moreover, cell viability results revealed that 4 mmol/L E-64 was not cytotoxic. This is a novel strategy to potentially prevent ASFV infection in pigs by blocking the activity of pS273R protease with a small-molecule inhibitor. African swine fever (ASF) is a viral disease in swine that results in high mortality in domestic pigs and causes considerable economic losses. The disease only affects humans exceptionally. Currently, there is no effective vaccine or drugs available for treatment. E64 is an epoxy monocarboxylic acid, a dicarboxylic acid monoamide, a member of guanidines and a L-leucine derivative. It has a role as a protease inhibitor, an antimalarial and an antiparasitic agent. ( https://doi.org/10.1016/j.bmc.2021.116055 )
* Forskolin-RepSox is a combination of the root extract forskolin and the small molecule RepSox — that can efficiently create large numbers of muscle stem cells. This chemical cocktail enabled muscle stem cells in elderly mice to overcome their adverse environment and launch a robust repair response. The approach would fix the genetic defect that causes Duchenne or other genetic muscular dystrophies. Forskolin is a potent activator of the adenylate cyclase system and the biosynthesis of cyclic AMP. From the plant Coleus forskohlii. Has antihypertensive, positive inotropic, platelet aggregation inhibitory, and smooth muscle relaxant activities; also lowers intraocular pressure and promotes release of hormones from the pituitary gland. RepSox is a potent and selective inhibitor of the TGF-β type 1 receptor (TGFβRI)/ALK5 that exhibits cell permeability and specifically inhibits ALK5 autophosphorylation with IC50 of 4 nM. RepSox has also been shown to contribute to the reprogramming of mouse embryonic fibroblasts to iPSCs, in addition to the induction of human fibroblasts into neuronal cells for research on Alzheimer’s disease. It has also been used as a basal media component for culturing human pluripotent stem cells.
* FTX-6058 is an investigational, potent, and selective small molecule inhibitor of Embryonic Ectoderm Development EED designed to increase the expression of fetal hemoglobin (HbF) with the potential to treat hemoglobinopathies, such as sickle cell disease and beta-thalassemia. Results from the MAD portion of the trial demonstrated proof of biology as evidenced by a dose proportional induction in HBG mRNA and accompanying increases in HbF-containing reticulocytes (F-reticulocytes). At 10mg, the highest dose studied to date, the mean changes were 4.5-fold and 4.2-fold, respectively. The increases in F-reticulocytes indicate that the HBG mRNA increases observed with FTX-6058 treatment are translating to HbF protein production. SCD is caused by mutations in the gene the encodes hemoglobin — the protein that carries oxygen in red blood cells. Current therapies are limited in efficacy, and new experimental gene therapies are only available to certain patients. FTX-6058 is designed to boost the production of fetal hemoglobin, improve oxygen transport, and alleviate disease symptoms. Higher doses of FTX-6058 effectively raised hemoglobin messenger RNA (mRNA) levels above those found at lower doses in healthy volunteers participating in a Phase 1 trial.
* Givinostat is a molecule being developed to treat Duchenne and Becker muscular dystrophies. It inhibits enzymes called histone deacetylases that turn off gene expression and can reduce a muscle’s ability to regenerate. Givinostat is currently being evaluated in a Phase 3 trial in Duchenne patients and a Phase 2 trial in Becker. Givinostat inhibits class I and class II histone deacetylases (HDACs) and several pro-inflammatory cytokines. This reduces expression of tumour necrosis factor (TNF), interleukin 1α and β, and interleukin 6. It also has activity against cells expressing JAK2(V617F), a mutated form of the janus kinase 2 (JAK2) enzyme that is implicated in the pathophysiology of many myeloproliferative diseases, including polycythaemia vera. In patients with polycythaemia, the reduction of mutant JAK2 concentrations by givinostat is believed to slow down the abnormal growth of erythrocytes and ameliorate the symptoms of the disease. Givinostat or gavinostat (originally ITF2357) is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities. Givinostat has been granted orphan drug designation in the European Union for the treatment of systemic juvenile idiopathic arthritis, polycythaemia vera. and Duchenne muscular dystrophy. The U.S. Food and Drug Administration has granted givinostat orphan drug, fast track, and rare pediatric disease designations for the treatment of DMD and BMD. A preclinical study produced early results suggesting the molecule might help with diastolic dysfunction.
* Ifetroban is a potent and selective thromboxane receptor antagonist. It has been studied in animal models for the treatment of myocardial ischemia, hypertension, stroke, thrombosis, cardiomyopathy, and for its effects on platelets. Ifetroban is being studied as a potential anti-fibrotic medication in several diseases but is not approved for and has never been studied in DMD patients. Studies in animal models of DMD showed oral ifetroban can prevent the scarring in the heart associated with Duchenne and improve survival compared to placebo. Cardiac function is a concern in Duchenne, as the heart is a muscle and is affected by the lack of dystrophin.
* Losmapimod is a potential treatment being for people with facioscapulohumeral muscular dystrophy (FSHD). FSHD is characterized by progressive weakness and wasting of muscles in the face, shoulders, and upper arms. Mutations in a specific region toward the end of chromosome 4, called the D4Z4 region, are known to contribute to a form of FSHD called FSHD1. These mutations lead to hypomethylation of a gene in the D4Z4 region called DUX4, the production of which is thought to adversely influence the activity of other genes in muscle cells, resulting in FSHD symptoms. Mutations in the DUX4 gene account for more than 90% of all FSHD cases. They cause excessive gene expression or activity, which leads to muscle degeneration and fat infiltration. Mitogen-activated protein kinases (MAPKs) are proteins that are activated as a cellular response to external stress, and have been shown to regulate the activity of the DUX4 gene. By inhibiting the activity of MAPKs using small molecules such as MAPK inhibitors, the overactive DUX4 gene can be controlled. Losmapimod is a selective MAPK inhibitor that has been seen in early studies to reduce DUX4 gene activity in FSHD patient-derived myotubes (fused muscle cells). Losmapimod does not affect the differentiation of myotubes or alter the production of other proteins in muscle cells. It is thought to inhibit the DUX4 gene and downstream pathways in a concentration-dependent manner in both FSHD1 and FSHD2.
* MBL Factor or mannose-binding lectin, also called mannan-binding lectin or mannan-binding protein (MBP), is a lectin that is instrumental in innate immunity as an opsonin and via the lectin pathway. MBL belongs to the class of collectins in the C-type lectin superfamily, whose function appears to be pattern recognition in the first line of defense in the pre-immune host. MBL recognizes carbohydrate patterns found on the surface of a large number of pathogenic micro-organisms, including bacteria, viruses, protozoa and fungi. Binding of MBL to a micro-organism results in activation of the lectin pathway of the complement system. Another important function of MBL is that this molecule binds senescent and apoptotic cells and enhances engulfment of whole, intact apoptotic cells, as well as cell debris by phagocytes. The complement system can be activated through three pathways: the classical pathway, the alternative pathway, and the lectin pathway. One way the most-recently discovered lectin pathway is activated is through mannose-binding lectin protein. MBL binds to carbohydrates (to be specific, D-mannose and L-fucose residues) found on the surfaces of many pathogens. For example, MBL has been shown to bind to: yeasts such as Candida albicans; viruses such as HIV and influenza A; many bacteria, including Salmonella and Streptococci; parasites like Leishmania; SARS-CoV-2 (Covid-19).
* Morin, is a natural compound with pro-osteogenic effects. Morin has an important pro-osteogenic effect in vivo that might facilitate osteoblast development and the production of osteoblast-related marker genes and in vitro protein markers for osteoblasts. In terms of molecular biology, morin contributes to osteoblast development and Wnt pathway stimulation through the activation and translocation of β-catenin nuclei. In short, morin can be a good bone substitute that can provide benefits for regenerating bone defect. The categories of bone fracture are the following: Closed or open fractures; complete fractures; displaced fractures; partial fractures; stress fractures. Some extra terms must also be added to describe partial, complete, open, and closed fractures. These terms include avulsion; comminuted; compression; impacted; oblique; spiral; transverse. Most often, bone fractures happen because the bone runs into a stronger force. Repetitive forces, such as running, can also fracture a bone (stress fractures). Another reason for fractures is osteoporosis, which weakens bones as you age. Internal fixation for nonunions should provide sufficient stability for fracture healing without excessive rigidity. The choice of internal fixation depends on the type of nonunion, the condition of the soft tissues and bone, the size and position of the bone fragments, and the size of the bony defect.
* Myriocin, also known as antibiotic ISP-1 and thermozymocidin, is a non-proteinogenic amino acid derived from certain thermophilic fungi. Myriocin is a very potent inhibitor of serine palmitoyltransferase, the first step in sphingosine biosynthesis. Due to this property, it is used in biochemical research as a tool for depleting cells of sphingolipids. Higher-than-normal sphingolipids levels are implicated in disorders that include Alzheimer’s disease, cardiovascular disease, diabetes, and obesity, in which sphingolipids are reported to accumulate in skeletal muscle and contribute to insulin resistance. Sphingolipid production is a potential therapy target for Duchenne muscular dystrophy DMD and combining blockers of sphingolipid production with glucocorticoids may be of more benefit than glucocorticoids alone.
* NEP1‑40 is a Nogo‑66 receptor antagonist peptide. Administration of NEP1‑40 attenuated the reduction of MBP, and upregulated GAP‑43 and MAP‑2 expression. MBP, a major constituent of CNS myelin, has been used as a marker of post-ischemic white matter injury and repair. GAP-43 and MAP-2 are molecular indicators of axonal plasticity in the CNS. NEP1‑40 ameliorated myelin damage and promoted regeneration by upregulating the expression of GAP‑43 and MAP‑2 related to neuronal and axonal plasticity, which may aid with the identification of a novel molecular mechanism of restriction in CNS regeneration mediated by Nogo‑A after ischemia in rats. Administration of NEP1-40 attenuates neurological deficits following ischemic stroke. Nogo-A is a potent inhibitor of neurite growth involved in regenerative failure, and neutralization of Nogo-A may allow for the generation of nerve growth and enhance structural reorganization in regions surrounding the lesions. However, the underlying molecular mechanism remains to be elucidated. NEP1-40 overexpression enhanced the ability of NSCs differentiation into neurons and promoted axon regeneration by inhibiting the Nogo-A/NgR1 signaling pathway.
* Pamrevlumab (FG-3019) is a fully human antibody designed to bind to and block the activity of connective tissue growth factor (CTGF), a pro-inflammatory protein that promotes wound healing and fibrosis (scarring), and is found at abnormally high levels in the muscles of DMD patients. Progressive, abnormal muscle fibrosis is a hallmark of muscular dystrophies, contributing to muscle weakness and injury, including to cardiac muscle — a major complication of DMD. By blocking CTGF, the therapy, administered directly into the bloodstream, is expected to suppress muscle fibrosis, thereby preventing the decline in patients’ motor, lung, and heart function, and possibly improving their status. The U.S. Food and Drug Administration has granted fast track designation to pamrevlumab, an investigational treatment for Duchenne muscular dystrophy (DMD). FG-3019 is already in clinical trials for other diseases involving fibrosis, including pulmonary fibrosis and kidney fibrosis.
* PRM-151 is an intravenous formulation of recombinant human pentraxin-2 in development for idiopathic pulmonary fibrosis (IPF) and myelofibrosis. Pentraxin-2, also referred to as serum amyloid P, has been found to inhibit apoptosis, airway inflammation, pulmonary fibrocyte accumulation, and collagen deposition driven by transforming growth factor beta-1. Pentraxin-2 also promotes macrophages associated with increased expression of interleukin-10 and interferon gamma-induced protein-10, which both possess anti-fibrotic properties.
* Rimeporide is an investigational treatment for Duchenne MD. The muscle cells of Duchenne patients have an overload of calcium, which is thought to be caused by dysfunctional NHE-1. Over time, high calcium concentrations contribute to the muscle damage that is seen in patients. Rimeporide inhibits NHE-1, thereby correcting calcium levels in the cell. A Phase 1b trial has been completed. Rimeporide was designed as a treatment for chronic heart failure. It was tested in seven Phase I studies clinical trials in patients with congestive heart failure and some degree of renal insufficiency. Subsequently, the drug was licensed to EspeRare, a Swiss nonprofit organisation that aims at repositioning drugs for rare diseases. As of May 2015, the substance has demonstrated efficacy in several animal models of Duchenne muscular dystrophy. It has also been recently tested in young boys with Duchenne muscular Dystrophy aged 6 to 11 years.
* THX-B is a small-molecule specific antagonist of p75(NTR). THX-B, has shown to restore normal bladder weight and voiding function in type 1 diabetic mice. Most importantly, the anti-inflammatory potency of p75NTR antagonism was demonstrated in the brain of mice with severe sepsis, supporting a molecular interplay between the p75NTR and TLR4 signaling axes in innerved tissues. Data suggests that p75NTR and TLR4 signaling axes form together cell-specific interplays in the bladder, p75NTR dysregulates bladder morphology and voiding. dysfunction, especially by interplaying with TLR4 signaling in infection.
( https://escholarship.mcgill.ca/concern/theses/wd376260w )
* UNR844 is a presbyopia drop from Novartis which uses lipoic acid choline ester 1.5% (an antioxidant) to break apart the disulfide bonds that form between proteins within the lens, and by doing so, increasing the lens flexibility and elasticity. What is unique about this drop is that it may have the potential to restore natural accommodation instead of just creating a pinhole effect like the miotic drops. In phase 1 and 2 studies, UNR844 demonstrated good initial results. All patients showed a substantial improvement in near acuity by day 15. At the end of three months, 82% of patients had 20/40 or better near vision and 36% had 20/25 or better. Therefore, the drop will likely be used twice a day for 90 days to achieve maximal effects. After discontinuing the drop after 90 days, the drug’s effects lasted up to 7 months without further dosing.
* Vamorolone is a dissociative steroid. It works in a similar way to other corticosteroids by activating certain pathways within the cell and inhibiting others. For example, it inhibits the NF-kB pathway, which is linked to inflammation. It also binds to and helps stabilize the membranes around cells without causing transactivation. Transactivation is the increase of gene expression that glucocorticoid response elements (GRES) cause. It results in many of the side effects of corticosteroid treatment. The benefit of Vamorolone, however, is that it is thought to have significantly fewer side effects than existing steroids, which can be life changing in themselves. Prednisone side effects include diabetes, high blood pressure, osteoporosis, short stature and weight gain. Vamorolone also may help preserve heart function in DMD patients through the inhibition of mineralocorticoid receptors. It also binds to and helps stabilize the membranes around cells without causing transactivation. Vamorolone also may help preserve heart function in Duchenne patients. Due to safety concerns related to the interaction between the muscle clock and drug-activated molecules, they should be administered at the start of the light period (approximately 7 am) to promote muscle function. Increased endurance and improved muscle mass and muscle force were lost when dosing occurred in the dark period.
* A-438079 is a selective P2X7 purinoceptor antagonist in both human and rat with minimal activity at 75 different G-protein-coupled receptors, enzymes, transporters, and ion channels tested. A-438079 molecule, one of the most potent and selective antagonists that competitively blocks P2X7 receptor in vitro activation and produces anti-nociceptive effects in in vivo settings. In addition to nociception, A438079 has already been successfully used in in vivo models of hyperalgesia, epilepsy, Parkinson’s disease, salivary gland exocrinopathy, and Charcot-Marie-Tooth 1A disease.
* Aceclidine is a small molecule acetylcholinesterase receptor agonist that causes pupil contraction, or miosis, creating a pinhole effect that improves near vision. Studies have shown that aceclidine’s mechanism of action is differentiated from competing therapeutic options due to its ability to create a pinhole pupil effect while avoiding myopic shift. It is crucial to minimize myopic shift as it can significantly impair distance vision for a majority of presbyopes. Aceclidine’s unique MOA, in which miosis is decoupled from myopic shift, is expected to allow it to target the broadest patient population. In the phase 2 trial, the near vision improvement was due to aceclidine’s ability to maintain a pinhole pupil sweet spot of 1.5 mm to 2 mm for 7 hours. There was no loss and a slight trend toward net gain in best corrected distance vision. In addition, aceclidine was well tolerated with most common side effect being mild discomfort on instillation and no serious adverse events. Aceclidine has been marketed in Europe but has not been used clinically in the United States. It is used in the treatment of open-angle glaucoma and is a parasympathomimetic agent.
* ANA-12 is a selective, small-molecule non-competitive antagonist of TrkB, the main receptor of brain-derived neurotrophic factor (BDNF). The compound crosses the blood-brain-barrier and exerts central TrkB blockade. It blocks the neurotrophic actions of BDNF without compromising neuron survival. ANA-12 produces rapid antidepressant- and anxiolytic-like effects in animal models, the former of which have been elucidated to be mediated by blockade of BDNF signaling in the nucleus accumbens. It has also been found to alleviate methamphetamine-induced depression-like behavior (including anhedonia), behavioral sensitization, and nucleus accumbens neuroplasticity changes with subchronic (14-day) administration in mice. ANA-12 blocks the cognitive-enhancing effects of environmental enrichment and calorie restriction in rodents, which are mediated by BDNF signaling through TrkB in the hippocampus. It also blocks hippocampal neurogenesis induced by physical exercise in rodents, and may block the cognitive-enhancing effects of exercise as well.
* ATX-LPA-LPARs Inhibitors. The ATX/LPA/LPARs axis could be part of an unexplored pro-fibrotic program in skeletal muscle pathologies causing muscular fibrosis such as DMD and Limb-girdle MD. Studies that modulate the function or the presence/absence of LPA receptors yielded the most promising results that suggest a role for the ATX/LPA/LPARs axis in fibrosis pathogenesis. There is increasing data suggesting that pharmacological blockage or genetic deletion of LPA receptors could prevent the development of induced fibrosis in different organs. The primary LPA receptors that appeared to be involved in fibrosis are LPA1 and LPA3. An increasing amount of evidence places LPA as a potent modulator of inflammation in different tissues such as lung, liver, cancer-related-organs, skeletal muscle such as in chronic injury of the rotator cuff muscles and, the heart in myocardial infarction. The recording plays the sound frequencies of PF-8380 (ATX inhibitor), Ki-16425 (LPA1 and LPA3 inhibitor), VPC-12259 (LPA1and LPA3 inhibitor) and, AM-095 (LPA1 inhibitor.)
-PF-8380 is a potent orally bioavailable inhibitor of autotaxin (ATX), the enzyme that synthesize lysophosphatidic acid (LPA) from lysophosphatidyl choline, and is an emerging target for treatment of inflammatory conditions, including cancer, arthritis and multiple sclerosis. PF-8380 blocks inflammation-induced LPA synthesis. PF-8380 works both in vitro and in vivo through direct inhibition of autotaxin. In human whole blood PF-8380 inhibited autotaxin with an IC50 of 101 nM.
-Ki-16425 is an antagonist of LPA1 and LPA3 receptors with moderate activity against LPA2. Ki-16425 inhibition of LPA receptors 1 and 3 prevents the induction of CCN2 by TGF-β. Ki16425 also downregulates the SMAD 2/3 proteins.
-VPC-12249 reduces collagen deposition and prevents the induction of pro-fibrotic cytokines such as CCN2 and TGF-β in the lung.
-AM-095, an LPA1 inhibitor, causes motor skills improvement evaluated by grip strength, rotarod, and runtime.
( https://doi.org/10.1007/s12079-021-00610-w )
* BMP6 Deficiency in diabetics causes delay in bone fracture consolidation. The categories of bone fracture are the following: Closed or open fractures; complete fractures; displaced fractures; partial fractures; stress fractures. Some extra terms must also be added to describe partial, complete, open, and closed fractures. These terms include avulsion; comminuted; compression; impacted; oblique; spiral; transverse. Most often, bone fractures happen because the bone runs into a stronger force. Repetitive forces, such as running, can also fracture a bone (stress fractures). Another reason for fractures is osteoporosis, which weakens bones as you age. Internal fixation for nonunions should provide sufficient stability for fracture healing without excessive rigidity. The choice of internal fixation depends on the type of nonunion, the condition of the soft tissues and bone, the size and position of the bone fragments, and the size of the bony defect.
* BMP9-Leptin when combined might improve fracture healing. The categories of bone fracture are the following: Closed or open fractures; complete fractures; displaced fractures; partial fractures; stress fractures. Some extra terms must also be added to describe partial, complete, open, and closed fractures. These terms include avulsion; comminuted; compression; impacted; oblique; spiral; transverse. Most often, bone fractures happen because the bone runs into a stronger force. Repetitive forces, such as running, can also fracture a bone (stress fractures). Another reason for fractures is osteoporosis, which weakens bones as you age. Internal fixation for nonunions should provide sufficient stability for fracture healing without excessive rigidity. The choice of internal fixation depends on the type of nonunion, the condition of the soft tissues and bone, the size and position of the bone fragments, and the size of the bony defect.
* Bocidelpar sulfate (ASP0367) is an orally administered small molecule that potently and selectively modulates peroxisome proliferator-activated receptor δ (PPARδ) to address mitochondrial dysfunction occurring in diseases including primary mitochondrial myopathy and Duchenne muscular dystrophy. The PPAR–δ pathway regulates mitochondria by turning on different genes in the cell. When the pathway is on, the mitochondria use fatty acids more often and more mitochondria are made. Using more fatty acids for energy results in increased energy production. Mitochondria are specialized structures within cells that supply chemical energy to power the activities of the cells, such as repairing muscle cells. Individuals with Duchenne lack efficient mitochondria in their cells. It is thought that by increasing or enhancing the mitochondria in muscle cells, the cellular functions of the muscle could be improved.
* Brimochol or Carbachol-Brimonidine tartrate is a miotic-based eye drop for presbyopia. Miotic agents like carbachol constrict the pupil to induce what’s called the “pinhole effect.” Similar to reducing the aperture of a camera, shrinking the pupil brings near images into clearer focus. Brimonidine dampens headache or brow ache, myopic shift, eye redness, or a loss of distance visual acuity reported by patients who take single-agent miotics. Brimonidine inhibits the contraction of the ciliary muscle, which means patients end up with a drug that gives them this meiosis, this pinhole effect, without the unwanted side effects. The effect could last at least eight hours. Carbachol is a parasympathomimetic that mimics the effect of acetylcholine on both the muscarinic and nicotinic receptors. This drug is administered ocularly to induce miosis to reduce intraocular pressure in the treatment of glaucoma. Carbachol is also used to stimulate micturition by contraction of detrusor muscle. This drug may cause hypotension, bradycardia, nausea, vomiting, bronchospasm, and abdominal cramps. Carbachol is an ammonium salt and a carbamate ester. It has a role as a nicotinic acetylcholine receptor agonist, a muscarinic agonist, a non-narcotic analgesic, a cardiotonic drug and a miotic. Cholinergic, parasympathomimetic, used chiefly in large animals, especially for colic in the horse. (EPA, 1998). Brimonidine tartrate is the tartrate salt form of brimonidine, an imidazole derivative and a selective alpha-2 adrenergic receptor agonist. Upon ocular administration, brimonidine tartrate acts on the blood vessels causing them to constrict which leads to a decrease in the production of aqueous humor. Brimonidine tartrate also enhances the outflow of aqueous humor. This drug is used in the treatment of glaucoma to reduce intraocular pressure. A quinoxaline derivative and adrenergic alhpa-2 receptor agonist that is used to manage intraocular pressure associated with open-angle glaucoma and ocular hypertension.
* C004019 is a small molecule designed on the basis of Proteolysis Targeting Chimera (PROTAC) to selectively enhance ubiquitination and proteolysis of tau proteins. C004019 robustly promotes tau clearance in multiple tau-overexpressing cell models via ubiquitination-proteasome pathway. Furthermore, both intracerebral and subcutaneous administration of C004019 could also remarkably reduce tau level in wild-type, human tau (hTau) transgenic and 3xTg-AD mouse models with simultaneous amelioration of synaptic and cognitive functions.Increasing evidence suggests that intracellular accumulation of tau plays a pivotal role in neurodegeneration and memory deficits in AD and the related neurodegenerative disorders, collectively termed tauopathies. The chimera is composed of three parts including a tau binder, a linker and an E3 ligase recruiter or Vhl binder, in which the two functional parts respectively binds to tau proteins and E3 ligase to reach a selective and efficient ubiquitination and the subsequent proteasome-mediated proteolysis of tau. In vitro and in vivo testing C004019 shows it efficiently induces clearance of tau proteins in both physiological and pathological conditions. Remarkably, even single-dose or infrequently (once per 6 days) subcutaneous administration of this molecule achieved a sustained tau reduction in the brain of hTau and 3xTg-AD transgenic mouse models. Lowering tau can alleviate Aβ-induced neurotoxicity, and knockdown of tau does not elicit obvious abnormalities in mice. ( https://www.thno.org/v11p5279.htm )
* CD2019 overcomes inhibition of axonal outgrowth via phosphoinositide 3-kinase signalling in the injured adult spinal cord. After spinal cord injury in the adult mammal, axons do not normally regrow and this commonly leads to paralysis. Retinoic acid (RA) can stimulate neurite outgrowth in vitro of both the embryonic central and peripheral nervous system, via activation of the retinoic acid receptor (RAR) beta2. Spinal cord injuries (SCIs) often result in permanent damage in the adult due to the very limited capacity of axonal regeneration. Intrinsic neuronal programs and the formation of a glial scar are the main obstacles. Activation of RARβ in the neuron inactivates phosphatase and tensin homolog and induces its transfer into the astrocytes in small vesicles, where it prevents scar formation.
* Coenzyme CoQ10 (ubiquinone) is present in all respiring eukaryotic cells, primarily in the mitochondria. It is a component of the electron transport chain and participates in aerobic cellular respiration, which generates energy in the form of ATP. Ninety-five percent of the human body's energy is generated this way. Organs with the highest energy requirements—such as the heart, liver, and kidney—have the highest CoQ10 concentrations. n a 2017 meta-analysis of people with heart failure 30–100 mg/d of CoQ10 resulted in 31% lower mortality. Exercise capacity was also increased. The Canadian Headache Society guideline for migraine prophylaxis recommends, based on low-quality evidence, that CoQ10 be offered as a choice for prophylaxis. A 2018 meta-analysis concluded that there was preliminary evidence for oral CoQ10 reducing statin-associated muscle symptoms, including muscle pain, muscle weakness, muscle cramps and muscle tiredness. CoQ10 may reduce the effectiveness of chemo and radiation therapy, so most oncologists would recommend avoiding it during cancer treatment. A 1995 review study found that there is no clinical benefit to the use of CoQ10 in the treatment of periodontal disease. When applied topically in skincare products it demonstrates some ability to reduce oxidative stress in the skin, delay signs of intrinsic skin aging, reverse signs of extrinsic skin aging, assist in fading dyspigmentation, increase stability of certain sunscreen actives, increase the SPF of sunscreens, and afford some infrared protection to sunscreens. Much of the research on the skin benefits of ubiquinone show that it works synergistically with other topical antioxidants to improve the skin and cosmetic formulations. Coenzyme Q10 has potential to inhibit the effects of theophylline as well as the anticoagulant warfarin; coenzyme Q10 may interfere with warfarin's actions by interacting with cytochrome p450 enzymes thereby reducing the INR, a measure of blood clotting. The structure of coenzyme Q10 is very similar to that of vitamin K, which competes with and counteracts warfarin's anticoagulation effects. Coenzyme Q10 should be avoided in patients currently taking warfarin due to the increased risk of clotting.
* D-Pantothenic Acid (pantothenate, vitamin B5) is a water-soluble vitamin ubiquitously found in plants and animal tissues with antioxidant property. Vitamin B5 is a component of coenzyme A (CoA) and a part of the vitamin B2 complex. Vitamin B5 is a growth factor and is essential for various metabolic functions, including the metabolism of carbohydrates, proteins, and fatty acids. This vitamin is also involved in the synthesis of cholesterol, lipids, neurotransmitters, steroid hormones, and hemoglobin. Only the dextrorotatory (D) isomer of pantothenic acid possesses biological activity. while the levorotatory (L) form may antagonize the effects of the dextrorotatory isomer.
* Duchenne Mix for Duchenne muscular dystrophy (DMD) is,
-Ubiquinone (co-enzyme Q10), a key component of an energy pathway in the mitochondria, called the electron transport chain.
-Edasalonexent, a small molecule that inhibits a protein called NF-kappa B in the NF-kappa B pathway. This pathway is activated in people with Duchenne muscular dystrophy (DMD), resulting in muscle fiber breakdown and the inability to repair muscle injuries.
-Ezutromid upregulates the production of utrophin to substitute for the deficiency of dystrophin in people with DMD. Utrophin upregulation is an actively researched therapeutic approach for the treatment of DMD. Utrophin is similar to dystrophin, but is produced only during embryonic development. It is hypothesized that increased utrophin during adulthood can compensate for the lack of dystrophin in DMD patients.
-MNK-1411 is the synthetic equivalent of the adrenocorticotropic hormone. It is a synthetic melanocortin agonist — a substance that acts like another substance, stimulating an action — that acts on melanocortin receptors. It delays the progression of DMD by modulating immune system activity and reducing muscle inflammation.
* E-64 is a small molecule inhibitor exhibiting the activity against African swine fever virus protease pS273R. The pS273R protein of the African swine fever virus (ASFV) is a specific SUMO-1-like cysteine protease that plays an important role in its replication process. To inhibit virus replication and improve treatment options the 14th carbon atom of the cysteinase inhibitor E-64 could form one Csingle bondS covalent bond with the Cys 232 amino acid of the pS273R protease and seven additional hydrogen bonds to maintain a stable binding state. E-64 could effectively inhibit the enzyme activity center of the pS273R protease by preventing pS273R protease from lysing pp62, while promoting the upregulation of immune-related cytokines at the transcription level. Moreover, cell viability results revealed that 4 mmol/L E-64 was not cytotoxic. This is a novel strategy to potentially prevent ASFV infection in pigs by blocking the activity of pS273R protease with a small-molecule inhibitor. African swine fever (ASF) is a viral disease in swine that results in high mortality in domestic pigs and causes considerable economic losses. The disease only affects humans exceptionally. Currently, there is no effective vaccine or drugs available for treatment. E64 is an epoxy monocarboxylic acid, a dicarboxylic acid monoamide, a member of guanidines and a L-leucine derivative. It has a role as a protease inhibitor, an antimalarial and an antiparasitic agent. ( https://doi.org/10.1016/j.bmc.2021.116055 )
* Forskolin-RepSox is a combination of the root extract forskolin and the small molecule RepSox — that can efficiently create large numbers of muscle stem cells. This chemical cocktail enabled muscle stem cells in elderly mice to overcome their adverse environment and launch a robust repair response. The approach would fix the genetic defect that causes Duchenne or other genetic muscular dystrophies. Forskolin is a potent activator of the adenylate cyclase system and the biosynthesis of cyclic AMP. From the plant Coleus forskohlii. Has antihypertensive, positive inotropic, platelet aggregation inhibitory, and smooth muscle relaxant activities; also lowers intraocular pressure and promotes release of hormones from the pituitary gland. RepSox is a potent and selective inhibitor of the TGF-β type 1 receptor (TGFβRI)/ALK5 that exhibits cell permeability and specifically inhibits ALK5 autophosphorylation with IC50 of 4 nM. RepSox has also been shown to contribute to the reprogramming of mouse embryonic fibroblasts to iPSCs, in addition to the induction of human fibroblasts into neuronal cells for research on Alzheimer’s disease. It has also been used as a basal media component for culturing human pluripotent stem cells.
* FTX-6058 is an investigational, potent, and selective small molecule inhibitor of Embryonic Ectoderm Development EED designed to increase the expression of fetal hemoglobin (HbF) with the potential to treat hemoglobinopathies, such as sickle cell disease and beta-thalassemia. Results from the MAD portion of the trial demonstrated proof of biology as evidenced by a dose proportional induction in HBG mRNA and accompanying increases in HbF-containing reticulocytes (F-reticulocytes). At 10mg, the highest dose studied to date, the mean changes were 4.5-fold and 4.2-fold, respectively. The increases in F-reticulocytes indicate that the HBG mRNA increases observed with FTX-6058 treatment are translating to HbF protein production. SCD is caused by mutations in the gene the encodes hemoglobin — the protein that carries oxygen in red blood cells. Current therapies are limited in efficacy, and new experimental gene therapies are only available to certain patients. FTX-6058 is designed to boost the production of fetal hemoglobin, improve oxygen transport, and alleviate disease symptoms. Higher doses of FTX-6058 effectively raised hemoglobin messenger RNA (mRNA) levels above those found at lower doses in healthy volunteers participating in a Phase 1 trial.
* Givinostat is a molecule being developed to treat Duchenne and Becker muscular dystrophies. It inhibits enzymes called histone deacetylases that turn off gene expression and can reduce a muscle’s ability to regenerate. Givinostat is currently being evaluated in a Phase 3 trial in Duchenne patients and a Phase 2 trial in Becker. Givinostat inhibits class I and class II histone deacetylases (HDACs) and several pro-inflammatory cytokines. This reduces expression of tumour necrosis factor (TNF), interleukin 1α and β, and interleukin 6. It also has activity against cells expressing JAK2(V617F), a mutated form of the janus kinase 2 (JAK2) enzyme that is implicated in the pathophysiology of many myeloproliferative diseases, including polycythaemia vera. In patients with polycythaemia, the reduction of mutant JAK2 concentrations by givinostat is believed to slow down the abnormal growth of erythrocytes and ameliorate the symptoms of the disease. Givinostat or gavinostat (originally ITF2357) is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities. Givinostat has been granted orphan drug designation in the European Union for the treatment of systemic juvenile idiopathic arthritis, polycythaemia vera. and Duchenne muscular dystrophy. The U.S. Food and Drug Administration has granted givinostat orphan drug, fast track, and rare pediatric disease designations for the treatment of DMD and BMD. A preclinical study produced early results suggesting the molecule might help with diastolic dysfunction.
* Ifetroban is a potent and selective thromboxane receptor antagonist. It has been studied in animal models for the treatment of myocardial ischemia, hypertension, stroke, thrombosis, cardiomyopathy, and for its effects on platelets. Ifetroban is being studied as a potential anti-fibrotic medication in several diseases but is not approved for and has never been studied in DMD patients. Studies in animal models of DMD showed oral ifetroban can prevent the scarring in the heart associated with Duchenne and improve survival compared to placebo. Cardiac function is a concern in Duchenne, as the heart is a muscle and is affected by the lack of dystrophin.
* Losmapimod is a potential treatment being for people with facioscapulohumeral muscular dystrophy (FSHD). FSHD is characterized by progressive weakness and wasting of muscles in the face, shoulders, and upper arms. Mutations in a specific region toward the end of chromosome 4, called the D4Z4 region, are known to contribute to a form of FSHD called FSHD1. These mutations lead to hypomethylation of a gene in the D4Z4 region called DUX4, the production of which is thought to adversely influence the activity of other genes in muscle cells, resulting in FSHD symptoms. Mutations in the DUX4 gene account for more than 90% of all FSHD cases. They cause excessive gene expression or activity, which leads to muscle degeneration and fat infiltration. Mitogen-activated protein kinases (MAPKs) are proteins that are activated as a cellular response to external stress, and have been shown to regulate the activity of the DUX4 gene. By inhibiting the activity of MAPKs using small molecules such as MAPK inhibitors, the overactive DUX4 gene can be controlled. Losmapimod is a selective MAPK inhibitor that has been seen in early studies to reduce DUX4 gene activity in FSHD patient-derived myotubes (fused muscle cells). Losmapimod does not affect the differentiation of myotubes or alter the production of other proteins in muscle cells. It is thought to inhibit the DUX4 gene and downstream pathways in a concentration-dependent manner in both FSHD1 and FSHD2.
* MBL Factor or mannose-binding lectin, also called mannan-binding lectin or mannan-binding protein (MBP), is a lectin that is instrumental in innate immunity as an opsonin and via the lectin pathway. MBL belongs to the class of collectins in the C-type lectin superfamily, whose function appears to be pattern recognition in the first line of defense in the pre-immune host. MBL recognizes carbohydrate patterns found on the surface of a large number of pathogenic micro-organisms, including bacteria, viruses, protozoa and fungi. Binding of MBL to a micro-organism results in activation of the lectin pathway of the complement system. Another important function of MBL is that this molecule binds senescent and apoptotic cells and enhances engulfment of whole, intact apoptotic cells, as well as cell debris by phagocytes. The complement system can be activated through three pathways: the classical pathway, the alternative pathway, and the lectin pathway. One way the most-recently discovered lectin pathway is activated is through mannose-binding lectin protein. MBL binds to carbohydrates (to be specific, D-mannose and L-fucose residues) found on the surfaces of many pathogens. For example, MBL has been shown to bind to: yeasts such as Candida albicans; viruses such as HIV and influenza A; many bacteria, including Salmonella and Streptococci; parasites like Leishmania; SARS-CoV-2 (Covid-19).
* Morin, is a natural compound with pro-osteogenic effects. Morin has an important pro-osteogenic effect in vivo that might facilitate osteoblast development and the production of osteoblast-related marker genes and in vitro protein markers for osteoblasts. In terms of molecular biology, morin contributes to osteoblast development and Wnt pathway stimulation through the activation and translocation of β-catenin nuclei. In short, morin can be a good bone substitute that can provide benefits for regenerating bone defect. The categories of bone fracture are the following: Closed or open fractures; complete fractures; displaced fractures; partial fractures; stress fractures. Some extra terms must also be added to describe partial, complete, open, and closed fractures. These terms include avulsion; comminuted; compression; impacted; oblique; spiral; transverse. Most often, bone fractures happen because the bone runs into a stronger force. Repetitive forces, such as running, can also fracture a bone (stress fractures). Another reason for fractures is osteoporosis, which weakens bones as you age. Internal fixation for nonunions should provide sufficient stability for fracture healing without excessive rigidity. The choice of internal fixation depends on the type of nonunion, the condition of the soft tissues and bone, the size and position of the bone fragments, and the size of the bony defect.
* Myriocin, also known as antibiotic ISP-1 and thermozymocidin, is a non-proteinogenic amino acid derived from certain thermophilic fungi. Myriocin is a very potent inhibitor of serine palmitoyltransferase, the first step in sphingosine biosynthesis. Due to this property, it is used in biochemical research as a tool for depleting cells of sphingolipids. Higher-than-normal sphingolipids levels are implicated in disorders that include Alzheimer’s disease, cardiovascular disease, diabetes, and obesity, in which sphingolipids are reported to accumulate in skeletal muscle and contribute to insulin resistance. Sphingolipid production is a potential therapy target for Duchenne muscular dystrophy DMD and combining blockers of sphingolipid production with glucocorticoids may be of more benefit than glucocorticoids alone.
* NEP1‑40 is a Nogo‑66 receptor antagonist peptide. Administration of NEP1‑40 attenuated the reduction of MBP, and upregulated GAP‑43 and MAP‑2 expression. MBP, a major constituent of CNS myelin, has been used as a marker of post-ischemic white matter injury and repair. GAP-43 and MAP-2 are molecular indicators of axonal plasticity in the CNS. NEP1‑40 ameliorated myelin damage and promoted regeneration by upregulating the expression of GAP‑43 and MAP‑2 related to neuronal and axonal plasticity, which may aid with the identification of a novel molecular mechanism of restriction in CNS regeneration mediated by Nogo‑A after ischemia in rats. Administration of NEP1-40 attenuates neurological deficits following ischemic stroke. Nogo-A is a potent inhibitor of neurite growth involved in regenerative failure, and neutralization of Nogo-A may allow for the generation of nerve growth and enhance structural reorganization in regions surrounding the lesions. However, the underlying molecular mechanism remains to be elucidated. NEP1-40 overexpression enhanced the ability of NSCs differentiation into neurons and promoted axon regeneration by inhibiting the Nogo-A/NgR1 signaling pathway.
* Pamrevlumab (FG-3019) is a fully human antibody designed to bind to and block the activity of connective tissue growth factor (CTGF), a pro-inflammatory protein that promotes wound healing and fibrosis (scarring), and is found at abnormally high levels in the muscles of DMD patients. Progressive, abnormal muscle fibrosis is a hallmark of muscular dystrophies, contributing to muscle weakness and injury, including to cardiac muscle — a major complication of DMD. By blocking CTGF, the therapy, administered directly into the bloodstream, is expected to suppress muscle fibrosis, thereby preventing the decline in patients’ motor, lung, and heart function, and possibly improving their status. The U.S. Food and Drug Administration has granted fast track designation to pamrevlumab, an investigational treatment for Duchenne muscular dystrophy (DMD). FG-3019 is already in clinical trials for other diseases involving fibrosis, including pulmonary fibrosis and kidney fibrosis.
* PRM-151 is an intravenous formulation of recombinant human pentraxin-2 in development for idiopathic pulmonary fibrosis (IPF) and myelofibrosis. Pentraxin-2, also referred to as serum amyloid P, has been found to inhibit apoptosis, airway inflammation, pulmonary fibrocyte accumulation, and collagen deposition driven by transforming growth factor beta-1. Pentraxin-2 also promotes macrophages associated with increased expression of interleukin-10 and interferon gamma-induced protein-10, which both possess anti-fibrotic properties.
* Rimeporide is an investigational treatment for Duchenne MD. The muscle cells of Duchenne patients have an overload of calcium, which is thought to be caused by dysfunctional NHE-1. Over time, high calcium concentrations contribute to the muscle damage that is seen in patients. Rimeporide inhibits NHE-1, thereby correcting calcium levels in the cell. A Phase 1b trial has been completed. Rimeporide was designed as a treatment for chronic heart failure. It was tested in seven Phase I studies clinical trials in patients with congestive heart failure and some degree of renal insufficiency. Subsequently, the drug was licensed to EspeRare, a Swiss nonprofit organisation that aims at repositioning drugs for rare diseases. As of May 2015, the substance has demonstrated efficacy in several animal models of Duchenne muscular dystrophy. It has also been recently tested in young boys with Duchenne muscular Dystrophy aged 6 to 11 years.
* THX-B is a small-molecule specific antagonist of p75(NTR). THX-B, has shown to restore normal bladder weight and voiding function in type 1 diabetic mice. Most importantly, the anti-inflammatory potency of p75NTR antagonism was demonstrated in the brain of mice with severe sepsis, supporting a molecular interplay between the p75NTR and TLR4 signaling axes in innerved tissues. Data suggests that p75NTR and TLR4 signaling axes form together cell-specific interplays in the bladder, p75NTR dysregulates bladder morphology and voiding. dysfunction, especially by interplaying with TLR4 signaling in infection.
( https://escholarship.mcgill.ca/concern/theses/wd376260w )
* UNR844 is a presbyopia drop from Novartis which uses lipoic acid choline ester 1.5% (an antioxidant) to break apart the disulfide bonds that form between proteins within the lens, and by doing so, increasing the lens flexibility and elasticity. What is unique about this drop is that it may have the potential to restore natural accommodation instead of just creating a pinhole effect like the miotic drops. In phase 1 and 2 studies, UNR844 demonstrated good initial results. All patients showed a substantial improvement in near acuity by day 15. At the end of three months, 82% of patients had 20/40 or better near vision and 36% had 20/25 or better. Therefore, the drop will likely be used twice a day for 90 days to achieve maximal effects. After discontinuing the drop after 90 days, the drug’s effects lasted up to 7 months without further dosing.
* Vamorolone is a dissociative steroid. It works in a similar way to other corticosteroids by activating certain pathways within the cell and inhibiting others. For example, it inhibits the NF-kB pathway, which is linked to inflammation. It also binds to and helps stabilize the membranes around cells without causing transactivation. Transactivation is the increase of gene expression that glucocorticoid response elements (GRES) cause. It results in many of the side effects of corticosteroid treatment. The benefit of Vamorolone, however, is that it is thought to have significantly fewer side effects than existing steroids, which can be life changing in themselves. Prednisone side effects include diabetes, high blood pressure, osteoporosis, short stature and weight gain. Vamorolone also may help preserve heart function in DMD patients through the inhibition of mineralocorticoid receptors. It also binds to and helps stabilize the membranes around cells without causing transactivation. Vamorolone also may help preserve heart function in Duchenne patients. Due to safety concerns related to the interaction between the muscle clock and drug-activated molecules, they should be administered at the start of the light period (approximately 7 am) to promote muscle function. Increased endurance and improved muscle mass and muscle force were lost when dosing occurred in the dark period.
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